State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Department of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China.
Viruses. 2019 Jan 9;11(1):39. doi: 10.3390/v11010039.
Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus with a crude mortality rate of ~35%. Previously, we established a human DPP4 transgenic (hDPP4-Tg) mouse model in which we studied complement overactivation-induced immunopathogenesis. Here, to better understand the pathogenesis of MERS-CoV, we studied the role of pyroptosis in THP-1 cells and hDPP4 Tg mice with MERS-CoV infection. We found that MERS-CoV infection induced pyroptosis and over-activation of complement in human macrophages. The hDPP4-Tg mice infected with MERS-CoV overexpressed caspase-1 in the spleen and showed high IL-1β levels in serum, suggesting that pyroptosis occurred after infection. However, when the C5a-C5aR1 axis was blocked by an anti-C5aR1 antibody (Ab), expression of caspase-1 and IL-1β fell. These data indicate that MERS-CoV infection induces overactivation of complement, which may contribute to pyroptosis and inflammation. Pyroptosis and inflammation were suppressed by inhibiting C5aR1. These results will further our understanding of the pathogenesis of MERS-CoV infection.
中东呼吸综合征冠状病毒（MERS-CoV）是一种高致病性病毒，粗死亡率约为 35%。此前，我们建立了人 DPP4 转基因（hDPP4-Tg）小鼠模型，在此模型中我们研究了补体过度激活诱导的免疫发病机制。在此，为了更好地了解 MERS-CoV 的发病机制，我们研究了细胞焦亡在感染 MERS-CoV 的 THP-1 细胞和 hDPP4-Tg 小鼠中的作用。我们发现 MERS-CoV 感染诱导人巨噬细胞发生细胞焦亡和补体过度激活。感染 MERS-CoV 的 hDPP4-Tg 小鼠脾脏中 caspase-1 过度表达，血清中 IL-1β 水平升高，提示感染后发生了细胞焦亡。然而，当用抗 C5aR1 抗体（Ab）阻断 C5a-C5aR1 轴时，caspase-1 和 IL-1β 的表达下降。这些数据表明，MERS-CoV 感染诱导补体过度激活，这可能导致细胞焦亡和炎症。抑制 C5aR1 可抑制细胞焦亡和炎症。这些结果将进一步加深我们对 MERS-CoV 感染发病机制的理解。
